US8129426B2 - Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof - Google Patents

Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof Download PDF

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Publication number
US8129426B2
US8129426B2 US11/989,135 US98913506A US8129426B2 US 8129426 B2 US8129426 B2 US 8129426B2 US 98913506 A US98913506 A US 98913506A US 8129426 B2 US8129426 B2 US 8129426B2
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artemisinin
type
water
hydroxy
compounds
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US20090298881A1 (en
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Ying Li
Jianping Zuo
Zhongshun Yang
Junxia Wang
Yu Zhang
Wei Tang
Jianxin Zhang
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Jiangsu Zuoyou Medicine Co Ltd
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to the chemosynthesis of terpenoid compounds and the immune inhibiting effect thereof, especially to novel artemisinin compounds, the preparation methods thereof, and the pharmaceutical compositions thereof as immunosuppressant.
  • Artemisinin is an antimalarial principle extracted from the traditional Chinese Medicine Qinghao ( Artemisia annua L.), and is a peculiar sesquiterpene lactone having a peroxy group. It has not only excellent antimalarial activity but also immunosuppressive effect.
  • artesunate possesses more powerful immune inhibiting effect than artemisinin and may be used to treat lupus erythematosus and some kinds of dermatoses effectively [YU Qibin et al., 56 Cases of Lupus Erythematosus Treated by Artesunate, Chinese Journal of Dermatology, 1997, 39: 51; Chen Hua et al., Clinical Observation on the Treatment for Eczema-Dermatitis and Photosensitivity Dermatosis with Artesunate, Bengbu Medical College Academic Journal, 1991, 16: 251].
  • the present inventors have discovered that a category of artemisinin derivatives containing a carboxylic acid group has a better immune inhibiting effect (Chinese Patent Application No.: 200510023824.1). However, they have sparing solubility in water, and probably poor bioavailability thereby. Thus, the present inventors continued to searching for more ideal immunosuppressants.
  • One object of the present invention is to provide a category of water-soluble artemisinin derivatives.
  • Another object of the present invention is to provide processes for their preparation.
  • Still another object of the present invention is to provide their medical use.
  • Still another object of the present invention is to provide their pharmaceutical compositions.
  • the present invention provides a compound represented by following formula (1), the isomers and pharmaceutic salts thereof:
  • X is OH
  • Y is H
  • Z is NH 2 , NHMe, NHEt, NHPr(n), NHBu, NHCH 2 CH 2 OH,
  • X is OH
  • Y is CH 3 or phenyl
  • Z is NH 2 , NHR, NHCH 2 CH 2 OH, NR′ 2 , NH(CH 2 ) 2-3 NMe 2 ,
  • R and R′ is a C 1 -C 4 alkyl.
  • the isomers of the compound represented by formula (1) include, but do not limit to, the stereoisomers and optical isomers.
  • the pharmaceutic salts of the compound represented by formula (1) include, but do not limit to, the addition salts with hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, oxalic acid, tartaric acid, citric acid, etc.
  • the compounds represented by formula (1) of the present invention are the following compounds:
  • n 0, X and Y is H, and Z is NH 2 ; or
  • n 1
  • X is OH
  • Y is H
  • Z is NHC 4 H 9 (t)
  • the substituted alcohol is glycidol
  • the substituted alcohol is propenol
  • the target compounds, free base may react with an organic acid or an inorganic acid in organic solvent, such as alcohol etc., to produce corresponding salts.
  • the compounds represented by formula (1) produced according to the method of the present invention may be refined through the conventional processes.
  • the present invention further provides pharmaceutical compositions having an immune inhibiting effect which contain the compound of formula (1) or its pharmaceutically acceptable salts in a safe and effective dose range and the pharmaceutically acceptable carriers.
  • the “safe and effective dose” means that the amount of the compound is sufficient to evidently improve the patients' condition but will not cause a serious side effect.
  • the safe and effective dose of the compound is determined according to the specific conditions, such as the age and weight of the subject, the adaptive diseases, the route of administration, the course of treatment and any other related therapy, etc. Generally, an adult is administered by 10 mg/day to 800 mg/day in a single dose or multiple doses. The dosage should be reduced accordingly for children.
  • the formulation of the said pharmaceutical composition is as following:
  • composition of the present invention can be administered through oral, parenteral, pemasal, perlingual, transocular, per respiratory tract or per rectum routines, especially as tablet or enteric coatel pill, injection water solution, sublingual tablet, patch, suppository, cream, ointment, gels for skin use, etc.
  • “Pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or excipients, which are suitable for human body and must have sufficient high purity and low toxicity. “Compatible” herein means that each component of the composition can be blended with the compound of the present invention or with each other without remarkably reducing the pharmacodynamic activity of the compound.
  • Some examples of pharmaceutically acceptable carrier includes sugars (e.g. glucose, sucrose, lactose, etc.), starch (e.g. maize starch, potato starch, etc.), cellulose and its derivatives (e.g.
  • emulsifier e.g. Tween®
  • moistening agent e.g. sodium dodecyl sulphate
  • coloring agent e.g. sodium dodecyl sulphate
  • flavoring agent e.g. sodium dodecyl sulphate
  • stabilizer e.g. sodium dodecyl sulphate
  • the inventors screened and studied the compounds of the present invention on their immunosuppressive activity in vitro and in vivo with the following methods (reference book: Modern Pharmacological Experimental Methods, Zhang Juntian ed., Beijing Medical University/Chinese Peking Union Medical University Union Press, 1998).
  • mice inbred Balb/c male mice, 6-8 weeks old.
  • RPMI-1640 culture solution Roswell Park Memorial Institure-1640 medium, from GibcoBRL, Life Technologies, USA
  • FBS fetal bovine serum
  • penicillin 100 U/mL
  • streptomycin 100 U/mL
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid
  • 2-ME 2-Mercaptoethanol
  • Concanavalin ConA
  • LPS bacterial Lipopolysaccharide
  • mice were killed by cervical dislocation, and their spleens were collected aseptically and levigated to form a single cell suspension; after removing erythrocytes with MTT solution (10% SDS (Sodium dodecyl sulfate) and 50% dimethylformamide, pH 7.2), the cell concentration was adjusted to 5 ⁇ 10 6 /mL with RPMI-1640 medium containing 10% FBS.
  • MTT solution 10% SDS (Sodium dodecyl sulfate) and 50% dimethylformamide, pH 7.2
  • MTT solution (10% SDS, 50% dimethylformamide; pH7.2) was added into each well, and after placed in incubator for 6-7 hours, OD 570 values was measured with a microplate reader at 570 nm.
  • mice were killed by cervical dislocation, and their spleens were collected aseptically and prepared into a single cell suspension.
  • the cell concentration was adjusted to 4 ⁇ 10 6 /mL with RPMI-1640 medium containing 10% FBS.
  • C57BL/6 and Balb/c mice were killed by cervical dislocation, and their spleens were collected aseptically and levigated into a single cell suspension. After removing the erythrocytes, the cell concentration was adjusted to 6 ⁇ 10 6 /mL with RPMI-1640 medium containing 10% FBS.
  • mice were challenged by application of 10 ⁇ L of 0.5% (v/v) DNFB on the inner and outer surfaces of the right ear on day 9;
  • Bovine collagen type II (CII, Collagen Research Center, Tokyo, Japan) was dissolved in 0.1N acetum and placed in a 4 ⁇ refrigerator overnight.
  • DBA/1 mice were immunized at the tail base with 125 ⁇ g of collagen emulsified in Freund's complete adjuvant (CFA) containing Mycobacterium tuberculosis strain H37Rv (Wako Pure Chemical Industries Ltd., Osaka, Japan) and boosted with the same preparations of collagen plus CFA 3 weeks later, but IFA was used as an adjuvant this time.
  • CFA Freund's complete adjuvant
  • H37Rv Mycobacterium tuberculosis strain
  • the experiment result was evaluated according to the following scores: 0: no reddish and swelling; 1: slightly swelling on toe joint; 2: swelling on toe joint and sole; 3: swelling on paw below ankle joint; 4: swelling on whole paw including ankle joint.
  • the total scores of four limbs for each animal represented the severity of CIA (collagen-induced arthritis).
  • the immune response activity mainly includes the cellular immunity mediated by T cells and the humoral immunity mediated by B cells.
  • the inhibitory effect of a drug on lymphocyte proliferation was evaluated with cell activation, division and proliferation when stimulating the cells directly with the T-cell mitogen Con A and the B-cell mitogen LPS in vitro.
  • the compounds were screened repeatedly on three concentrations of 10 ⁇ m, 1 ⁇ m and 0.1 ⁇ m.
  • the compounds of examples 1, 11 and 14 showed obvious immune inhibitory activities with a concentration without any cytotoxicity, and their inhibiting rates to T-cell proliferation (Con A) were 65%, 48% and 52% respectively, their inhibiting rates to B-cell proliferation (LPS) were 73%, 99% and 81% respectively.
  • the compounds of example 2, 3 and 12 with a concentration without any cytotoxicity, had the inhibiting rates to T-cell proliferation (Con A) of 48%, 47% and 47% respectively and the inhibiting rates to B-cell proliferation (LPS) of 48%, 51% and 47% respectively;
  • the compounds of example 8, 16, 17 and 18, with a concentration without any cytotoxicity had the inhibiting rates to T-cell proliferation (Con A) of 13%, 0%, 6% and 9% respectively and the inhibiting rates to B-cell proliferation (LPS) of 42%, 51%, 24% and 26% respectively, this result indicated that these four compounds had a stronger inhibiting activity for B-cell proliferation, but less or no inhibiting activity for T-cell proliferation with a concentration without any cytotoxicity.
  • the compounds of example 1, 11 and 14 were selected to be further experimented on their pharmacological activity of immunodepression in vitro and in vivo.
  • the alloantigen is the main factor causing the rejection reaction of organism after blood transfusion and organ transplantation.
  • the alloantigen expressed on the heterogenous lymphocytes mainly are the histocompatibility antigen MHC-I and MHC-II molecules, which stimulate the response T cells to induce the immune proliferation reaction.
  • the pharmacologic effect of drugs on immune system response which is more resemble to the physiological conditions, is evaluated by the effect of the drugs on MLR.
  • the compounds of examples 1, 11 and 14 remarkably inhibited the proliferation of the response lymphocytes in MLR, and their EC50 values are 3.48 ⁇ 0.72 ⁇ M, 0.59 ⁇ 0.066CM and 0.67 ⁇ 0.012 ⁇ M respectively.
  • mice DTH response model was employed to further examine the immune pharmacological activity of the compounds of examples 1, 11 and 14 in vivo.
  • the results showed that the compounds of examples 1, 11 and 14 could obviously inhibit the swelling of the ear of mice (p ⁇ 0.01) when being administered orally with an amount of 50 mg/kg, 100 mg/kg and 50 mg/kg respectively, and their inhibiting rates were 56.5%, 50.5% and 52.2% respectively compared with the control group, which is comparative with the pharmacological activity of cyclosporine A(CsA) (5 mg/kg), an inhibiting rate of 40.6%.
  • the compounds of example 1 and example 14 were further tested of the immune pharmacological activity in the mice arthritis model. The results indicated that the compounds of example 1 and example 14 could obviously reduce the swelling of the mice' joints (p ⁇ 0.05) when being taken orally with an amount of 1 mg/kg and 0.5 mg/kg respectively.
  • FIG. 1 is a graph showing the thickness difference of swelling on ears, in which the compounds of example 1, example 11 and example 14 obviously reduced the swelling degree on ears of the DTH mice.
  • FIG. 2 is a graph showing the weight difference of ear slices, in which the compounds of example 1, example 11 and example 14 obviously reduced the weight of swelling ears of the DTH mice.
  • FIG. 3 is a graph showing the scorings of the arthritis degree with and without the compound of example 1, which indicates the compound of example 1 can prevent and cure the mice arthritis induced by bovine collagen type II and inhibit the swelling of the sicked joints.
  • FIG. 4 is a graph showing the scorings of the arthritis degree with and without the compound of example 14, which indicates the compound of example 14 can prevent and cure the mice arthritis induced by bovine collagen type II and inhibit the swelling of the sicked joints.
  • artemisinin nucleus is represented by Q:
  • the ripple line represents ⁇ substitution or/and a substitution
  • the dash line represents a substitution
  • the active component was pulverized, and screened with 100 mesh sieve; after mixed with sodium hydroxylmethyl cellulose and 10% starch paste, granulation and drying were carried out. Then the dry starch and lubricant was added into and mixed uniformly; tabletting was performed to obtain the final product.
  • the active component was pulverized and screened; after mixed uniformly with microcrystalline cellulose and lubricant, tabletting was performed immediately to obtain the final product.
  • the active component was mixed uniformly with starch, and 10% starch paste was added to prepare the damp mass, then granulation, drying, and pelletization are processed. After dry starch and talc powder were further added, tabletting and coating with an enteric coating were performed to obtain the final product.
  • the active component and the auxiliary materials are homogeneously mixed and packed into empty capsula to obtain the final product.
  • Polyethylene glycol 300 and polyethylene glycol 1500 were agitated and heated to be molten, then the active component after being pulverized and sieved was added, and mixed homogenously to obtain a gel product.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicinal Preparation (AREA)
US11/989,135 2005-07-22 2006-07-20 Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof Active 2027-01-21 US8129426B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN200510028056 2005-07-22
CNA2005100280569A CN1900081A (zh) 2005-07-22 2005-07-22 水溶性青蒿素衍生物、制法、药物组合物及用途
CN200510028056.9 2005-07-22
PCT/CN2006/001782 WO2007009388A1 (fr) 2005-07-22 2006-07-20 Derives d'artemisinine hydrosolubles, leurs procedes de preparation, leurs compositions pharmaceutiques et leur utilisation

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US20090298881A1 US20090298881A1 (en) 2009-12-03
US8129426B2 true US8129426B2 (en) 2012-03-06

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US (1) US8129426B2 (de)
EP (1) EP1911761B1 (de)
JP (1) JP5345390B2 (de)
CN (2) CN1900081A (de)
WO (1) WO2007009388A1 (de)

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EA021061B1 (ru) * 2009-09-11 2015-03-31 Санофи Способ производства промежуточных продуктов артемизинина
US8815942B2 (en) 2010-10-20 2014-08-26 The Royal Institution For The Advancement Of Learning/Mcgill University Combination therapy and uses thereof for treatment and prevention of parasitic infection and disease
CN103497200B (zh) * 2013-08-13 2016-06-08 北京联合大学生物化学工程学院 一种二氢青蒿素高级脂肪酸酯及其制备方法
CN103664982A (zh) * 2013-12-06 2014-03-26 湖南科源生物制品有限公司 青蒿素类似物及其制备方法
CN108653272B (zh) * 2017-03-31 2022-09-20 中国科学院上海药物研究所 青蒿素类衍生物在制备用于治疗炎症性肠病的药物中的用途
CN109020992B (zh) * 2017-06-09 2024-04-12 华东理工大学 一种立体选择性制备β型单/双青蒿烷基醚胺马来酸盐的方法
CN110343117B (zh) * 2018-04-04 2023-06-09 中国科学院上海药物研究所 青蒿素衍生物的制备方法
CN110559329A (zh) * 2019-09-19 2019-12-13 重庆市中药研究院 一种含双氢青蒿素与火把花的药物组合物、制剂及其制备方法
CN112315956A (zh) * 2020-08-26 2021-02-05 同济大学 9,10-脱水二氢青蒿素的预防和治疗多发性硬化症药物应用
CN114668758A (zh) * 2021-05-17 2022-06-28 澳门大学 青蒿素及其衍生物在制备ChAT活性增强剂中的应用
CN114933603A (zh) * 2022-06-10 2022-08-23 上海英诺富成生物科技有限公司 一种青蒿素的衍生物及其制备方法与应用

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CN101223177B (zh) 2011-11-16
JP5345390B2 (ja) 2013-11-20
CN1900081A (zh) 2007-01-24
CN101223177A (zh) 2008-07-16
JP2009502752A (ja) 2009-01-29
US20090298881A1 (en) 2009-12-03
EP1911761B1 (de) 2014-10-15
WO2007009388A1 (fr) 2007-01-25
EP1911761A1 (de) 2008-04-16

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